Radical hydroacylation of CC and NN double bonds in air

135 Pages·2011·4.18 MB·English

University College London

Radical Hydroacylation of C-C
and N-N Double Bonds in Air

by

Jenna Marie Ahern

Submitted in partial fulfilment of the requirements for the degree of

Doctor of Philosophy
Declaration
I, Jenna Marie Ahern, confirm that the work presented in this thesis is my own.
Where information has been derived from other sources, I confirm that this has been
indicated in the thesis.

Jenna Marie Ahern
October 2010
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Abstract
The formation of C-C and C-N bonds in modern organic synthesis is a key target for
methodological advancement. Current methods of C-C and C-N bond formation
often involve the use of expensive catalysts, or sub-stoichiometric reagents, which
can lead to the generation of undesirable waste products. This thesis describes a
novel and environmentally benign set of reaction conditions for the formation of C-C
and C-N bonds by hydroacylation and this is promoted by mixing two reagents, an
aldehyde and an electron-deficient double bond, under freely available atmospheric
oxygen at room temperature
Chapter 1 will provide an introduction to the thesis and mainly discusses methods for
C-C bond formation, in particular, radical chemistry and hydroacylation. Chapter 2
describes the hydroacylation of vinyl sulfonates and vinyl sulfones (C-C double
bonds) with aliphatic and aromatic aldehydes with a discussion and evidence for the
mechanism of the transformation. Chapter 3 details the synthesis of precursors for
intramolecular cyclisations and studies into aerobic intramolecular cyclisations.
Chapter 4 describes the hydroacylation of vinyl phosphonates (C-C double bonds)
and diazocarboxylates (N-N double bonds) with aliphatic and aromatic aldehydes
bearing functional groups. In addition, the hydroacylation of diazocarboxylates with
chiral aldehydes will be discussed.
In conclusion, a new, facile and clean set of reaction conditions for the formation of
C-C and C-N bonds has been developed via aerobic C-H activation of aldehydes
providing access to unsymmetrical ketones.
ii
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Contents
Declaration i
Abstract ii
Contents iii
Acknowledgments v
Abbreviations vi
Chapter 1! Introduction 1!
1.1! Discovery and history of free radicals 1!
1.2! Comparison between radical and ionic reactions 2!
1.3! Radical chain reactions 3!
1.3.1! Trialkyltin radicals as chain carriers 4!
1.4! Radical chemistry in synthesis 5!
1.4.1! Radical initiators 6!
1.4.2! Non-tin based radical chain carriers 8!
1.4.3! Radical chemistry in complex molecule synthesis 10!
1.5! Hydroacylation 12!
1.5.1! Transition metal catalysed hydroacylation 12!
1.5.2! Hydroacylation in ionic liquids 15!
1.5.3! Stetter reaction 15!
1.6! Chemistry of acyl radicals 16!
1.6.1! Acyl radicals via carbonylation of alkyl radicals 17!
1.6.2! Acyl radicals from telluro- and seleno-esters 17!
1.7! Acyl radicals from acid chlorides 18!
1.7.1! Hydroacylation via acyl radicals 18!
1.7.2! Intramolecular acyl radical additions to C-C double bonds 23!
1.7.3! Intramolecular acyl radical additions to C-N double bonds 24!
1.8! Chemistry ‘in the presence of water’ 25!
1.9! Radical reactions using aryl vinyl sulfonates 26!
1.9.1! Functionalisation of vinyl sulfonates via alkyl radical additions 26!
1.9.2! Hydroacylation of vinyl sulfonates 27!
1.10! Aims 28!
Chapter 2! Hydroacylation of vinyl sulfonates and sulfones 29!
2.1! Introduction 29!
2.2! Optimisation studies for hydroacylation of vinyl sulfonates 29!
2.3! Aldehyde scope for hydroacylation of vinyl sulfonates 32!
2.3.1! Hydroacylation of alternative vinyl sulfonates 36!
2.4! Reaction mechanism 36!
2.5! Further optimisation for hydroacylation of vinyl sulfonates 38!
2.6! Hydroacylation of vinyl sulfonates using aromatic aldehydes 40!
2.6.1! Auto-oxidation study on aromatic aldehydes 41!
2.6.2! Hydroacylation of PFP vinyl sulfonate with aromatic aldehydes 43!
iii
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

2.6.3! Optimisation of the hydroacylation of aromatic aldehydes 45!
2.7! Hydroacylation of vinyl sulfones 47!
2.7.1! Aldehyde scope 47!
2.8! Conclusions 49!
Chapter 3! Studies on intramolecular hydroacylation of electron
deficient alkenes 51!
3.1! Introduction and synthetic approach 51!
3.2! Synthesis of cyclisation precursors 52!
3.2.1! Synthesis of vinyl sulfonate bearing an aliphatic aldehyde 52!
3.2.2! Synthesis of vinyl sulfonate bearing aromatic aldehyde 55!
3.3! Synthesis of vinyl sulfone bearing an aliphatic aldehyde 56!
3.4! Cyclisation studies 57!
3.4.1! Cyclisation of sulfonate ester 222 57!
3.4.2! Cyclisation of sulfone 236 58!
3.5! Conclusions 59!
Chapter 4! Hydroacylation of vinyl phosphonates and azodicarboxylates
60!
4.1! Introduction 60!
4.2! Hydroacylation of vinyl phosphonates 60!
4.2.1! Preparation of substituted vinyl phosphonates 61!
4.3! Hydroacylation of azodicarboxylates 62!
4.3.1! Introduction 62!
4.3.2! Hydroacylation of DIAD 63!
4.3.3! Aldehyde tolerance for hydroacylation of DIAD 64!
4.3.4! Hydroacylation of DIAD with chiral aldehydes 67!
4.4! Conclusions 72!
Conclusions and Further Work 74!
Experimental 76!
General Experimental 76!
Experimental for Chapter 2 77!
Experimental for Chapter 3 91!
Experimental for Chapter 4 99!
References 121!
iv
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Acknowledgments
First and foremost, I would like to express my thanks to Prof. Stephen Caddick for
the opportunity to work on such an exciting project for the last 3 years and for his
continued support through my ups and downs. Dr Richard Fitzmaurice deserves a
huge thank you for the help he provided me throughout my PhD (especially at the
start) and his continued patience with me. I am also extremely grateful to Richard
and Dr Anne Mortimer for proofreading this thesis.
I would like to thank the members of the Caddick group who were there during my
PhD with special thanks to Vijay Chudasama for picking me up in my second year
and giving me constant motivation until the end. Vijay has been a great friend and a
great chemist to work with over the past couple of years – the Caddick group are
lucky to have you.
I would like to thank Abil Aliev, not only for this never-ending help with NMR, but
also for his supply of chocolates. In addition, I would like to thank Lisa Harris for
her continued efforts in mass spectroscopy. Another thank you (and goodbye) to
Dave Rowley, Dewi Lewis, Mike Porter, Helen Hailes, Willie Motherwell and Jon
Wilden for good friendship and laughs over the past 7 years at UCL - you will be
especially missed.
I am also forever grateful to my best friend, Adam Ellwood – a true friend who has
always stuck by me through everything. Another great friend who I’d like to thank is
Annie Pooutides for telling me I’d get through it when times got hard – I’m forever
grateful for your friendship. And not to be missed – Lobo (aka the lobotron), just
one more year left, good luck!
Finally, thank you to my mum who has always supported me and thank you to my
dad who was with me in spirit.

v
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Abbreviations
[!] Specific rotation
D
AIBN Azobis(isobutyronitrile)
ACCN Azobis(cyclohexanecarbonitrile)
BPO Dibenzoyl peroxide
CO Carbon monoxide
DABCO 1,4-diazabicyclo[2.2.2]octane
DCM Dichloromethane
DEPT Distortionless enhancement by polarisation transfer
DIAD Diisopropyl azodicarboxylate
DIBAL Diisobutylaluminium hydride
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
E Entgegen (opposite, trans)
ee Enantiomeric excess
EPHP 1-Ethyl-piperidine hypophosphite
EWG Electron-withdrawing group
HOMO Highest occupied molecular orbital
HPLC High-performance liquid chromatography
KHMDS Potassium hexamethyldisilazide
LDA Lithium diisopropylamide
LHMDS Lithium hexamethyldisilazide
LUMO Lowest unoccupied molecular orbital
m.p Melting point
MTG Methyl thioglycolate
vi
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

NHPI N-hydroxyphthalimide
NMR Nuclear magnetic resonance
PCC Pyridinium chlorochromate
PFP Pentafluorophenyl
PPTS Pyridinium p-toluenesulfonate
rt Room temperature
S 2 Bimolecular nucleophilic substitution
N
SOMO Singly occupied molecular orbital
TBAF tetra-n-Butylammonium fluoride
TBHN Di-tert-butyl hyponitrite
TBS tert-Butyldimethylsilyl
TBSCl tert-Butyldimethylsilyl chloride
TCP Trichlorophenyl
TDT tert-Dodecanethiol
TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl
THF Tetrahydrofuran
TLC Thin layer chromatography
TTMSS Tris(trimethylsilyl)silane
UCL University College London
Z Zusammen (together, cis)
vii
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Chapter 1 Introduction
Radical reactions have become important since the discovery of the triphenylmethyl
radical over a century ago.1 Radical chemistry complements traditional ionic
methods used in organic synthesis as typically they are carried out under neutral
reaction conditions, which are tolerated by a wide range of functional groups and
they are often insensitive to the type of solvent used. This contrasts to ionic
reactions, which often show poorer functional group tolerance and can be critically
dependent on correct choice of solvent and sensitive to solvation effects. For
example, an S 2 displacement can be accelerated by a factor of 106 by the use of a
N
polar aprotic solvent in replace of a protic one. It is also worth noting one important
general advantage of free-radical reactions is that because of their ambiphilic nature,
they can react with both electron rich and electron poor substrates.
1.1 Discovery and history of free radicals
The pioneering study into free radical chemistry was conducted by Gomberg in
1900.2,3 Whilst investigating the reaction of chlorotriphenylmethane (1) with various
metals, Gomberg found that, instead of obtaining expected radical recombination
product 2, dialkyl peroxide 3 was isolated instead, whereby oxygen had been
incorporated into the product, via reaction of tertiary radical 4 with molecular oxygen
(Scheme 1). When an analogous reaction was carried out under an atmosphere of
carbon dioxide, triene 5, derived from radical recombination of triphenylmethane
radical 4 and 6, was isolated. Intriguingly, intermediate triphenylmethane radical 4
does not combine to give dimer 2, and has since been described as being of the class
of radicals termed ‘persistent’. Persistent radicals are long-lived species that
recombine very slowly due to steric crowding around the radical centre. However,
such radicals will recombine rapidly with radicals of a different kind e.g. in the case
of triphenylmethane radical 4, recombination with molecular oxygen to give
peroxide 3 is rapid

1
Radical Hydroacylation of C-C and N-N Double Bonds in Air Jenna Marie Ahern

Ph Metal Ph Recombine PhPh
Ph Cl Ph X Ph Ph
reduction
Ph Ph PhPh
1 4 2
O No O
2 2
Ph Ph
Ph Ph
Ph O O Ph
Ph C
3
Ph Ph Ph Ph
3 6 5
Scheme 1 Attempted synthesis of hexaphenylethane 2
Despite the initial discovery by Gomberg, the significance of radical chemistry was
not realised by chemists until around three decades later. At this time, Kharasch and
co-workers discovered that when an olefin 7 was subjected to hydrogen bromide in
the absence of oxygen, the ionic Markovnikov product 8 prevails.4 However, in the
presence of molecular oxygen, anti-Markovnikov product 9 was obtained via radical
intermediate 10 (Scheme 2).
HBr Br H
R (No O2) R
7 8
HBr O
2
Br HBr H Br
R R
10 9
Br
Scheme 2 Formation of Markovnikov and anti-Markovnikov products from hydrobromination of
terminal alkene 7
1.2 Comparison between radical and ionic reactions
One of the main difficulties in utilising radical reactions is that synthetically useful
free-radicals are highly reactive, short-lived species and often undergo undesired
side-reactions.5 Ionic reactions on the other hand utilise intermediates that can often
be more stable and hence survive for longer periods allowing the desired reaction to
take place. Due to the reactivity of radical species, dimer formation (mainly primary
and secondary radicals) or disproportionation (mainly tertiary radicals) can be a
problem. In order to try and prevent these problems, the concentration of radical
species can be kept low to and avoid dimerisation and allow the radical species to
2